Tesofensine and diet may produce greater weight loss than other approved drugs

Combined with diet, tesofensine may be superior to currently approved weight loss drugs in reducing weight among patients with obesity.

To determine the safety and efficacy of the serotonin-noradrenaline-dopamine reuptake inhibitor, researchers from the University of Copenhagen conducted a phase-2, randomized, double-blind, placebo-controlled trial at five obesity management centers.

The study included 203 obese participants (BMI 30 to ≤40 kg/m²) aged between 18 and 65 years. After a two-week dietary run-in period, participants were randomly assigned to an energy-restricted diet and tesofensine 0.25 mg (n=52), 0.5 mg (n=50), 1 mg (n=49) or placebo (n=52) once per day for 24 weeks. The primary outcome measure was the percentage change in bodyweight.

Seventy-nine percent of participants completed the 34-week study. At the end of the treatment period, diet and placebo reduced weight loss by a mean of 2%. Mean weight loss for tesofensine and diet was greater than placebo and diet by 4.5% for 0.25 mg, 9.2% for 0.5 mg and 10.6% for 1 mg (P<.0001).

Compared with placebo, the number of participants in the tesofensine 1 mg group who had a weight loss of ≥5 kg was more than three times higher (P<.0001). Similarly, the proportion of participants who lost 10 kg or more of initial bodyweight was about 10-times higher in the tesofensine 1 mg group compared with placebo (P<.0001).

“Weight loss produced above that of diet and placebo during six to 12 months was 3 kg for orlistat (Xenical, Roche), 4.5 kg for sibutramine (Meridia, Abbott Laboratories), and 4.7 kg for rimonabant. Weight loss produced with tesofensine was 10 kg,” Arne Vernon Astrup, MD, professor in the Department of Human Nutrition and Faculty of Life Sciences at the University of Copenhagen, told Endocrine Today.

Non-obesity-related effects

Tesofensine also reduced fasting triglyceride and total cholesterol concentrations; however, a significant decrease in LDL cholesterol was achieved only with the 0.25 mg dose.

At the end of the treatment period, no significant increases in blood pressure were reported with tesofensine 0.25 mg or 0.5 mg compared with placebo; however, the researchers reported the heart rate among patients in the tesofensine 0.5 mg group was 7.4 beats per minute higher (P=.0001).

“We conclude that tesofensine 0.5 mg, once daily for six months, has the potential to produce twice the weight loss as currently approved drugs; however, larger phase-3 studies are needed to substantiate our findings,” the researchers wrote.

Dry mouth, nausea, constipation, hard stools, diarrhea and insomnia were the most commonly reported adverse events associated with tesofensine.

Anger and hostility increased with tesofensine 1 mg (P=.018) and confusion increased with both 0.5 mg and 1 mg doses (P=.015). Compared with placebo, tesofensine improved vigor and activity (P=.0093 for 0.25 mg, P=.0002 for 0.5 mg and P=.0003 for 1 mg).

Total weight-related quality of life scores were higher in the tesofensine group: 16.9% improvement for 0.25 mg (P=.02) and 20.8% improvement for both 0.5 mg (P=.005) and 1 mg (P=.007) compared with a 3.2% improvement for placebo.

According to Astrup, Neurosearch, a Scandinavian biopharmaceutical company, has planned a phase-3 trial for early 2009. – by Stacey L. Adams

Lancet. 2008;doi:10.1016/S0140-6736(08)61525-1.